Extended-release naltrexone (XR-NTX) reduces overdose risk and is filling a niche for opioid addicted patients that do not want agonist maintenance or cannot access it. However transitioning to naltrexone requires detoxification, which is a major hurdle. Methadone or buprenorphine tapers are effective but require a 7 to 14-day opioid-free interval before starting naltrexone, leaving ample time to relapse. Non-opioid detoxification with an alpha-2 adrenergic receptor agonist may shorten the time, and lofexidine was recently approved for this indication. It is safer than clonidine however like clonidine, it does not reduce the subjective effects of withdrawal and patients do not like it. A medication that better targets these symptoms may improve outcomes and increase the proportion that transition to XR-NTX. Pregabalin may be such a medication. It potentiates the activity of glutamic acid decarboxylase, inhibits calcium influx and release of excitatory neurotransmitters, raises GABA levels, and is approved for neuropathic pain, fibromyalgia, adjunctive therapy for adults with partial onset seizures and in Europe, for anxiety. It was not controlled in Russia for several years but was placed on their equivalent of our Schedule V due to reports that opioid addicted persons were using it to reduce withdrawal and abuse. Based on this information, Krupitsky and colleagues randomized 34 consenting, heroin-addicted inpatients under double-blind conditions to pregabalin or clonidine-based detoxification protocols. More pregabalin than clonidine patients completed detoxification (p = 0.01) and pregabalin patients had better retention than clonidine patients (p = 0.001) with no differences in adverse events. Here we propose to see if pregabalin can be combined with lofexidine to better reduce the subjective effects of opioid withdrawal than lofexidine, and increase the proportion that transition to XR-NTX. Such a dosing combination could lower the detoxification hurdle for patients who are interested in antagonist treatment or who are in settings where it is unavailable or difficult to access. This work will require two phases, and both fit into the UG3/UH3 announcement. In UG3 we will study pregabalin/lofexidine combinations to identify one that reduces withdrawal-related subjective effects without generating more serious adverse events than lofexidine alone. In UH3 we will test that combination in an adequately powered trial to determine if it increases the number of patients that complete detoxification and transition to XR-NTX. Hypotheses are that we will identify a dosing combination that is safe and reduces opioid withdrawal to a greater degree than lofexidine alone, and that this lofexidine/pregabalin combination will result in more patients completing detoxification and transitioning to XR-NTX. The ultimate goal is to generate data to support new or modified indications(s) and/or inclusion of new recommendations in product prescribing information to improve detoxification outcome and increase the proportion that transition to XR-NTX